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Relaxin reduces endothelium-derived vasoconstriction in hypertension: Revealing new therapeutic insights.

松弛素减少高血压内皮源性血管收缩: 揭示新的治疗见解。

  • 影响因子:6.12
  • DOI:10.1111/bph.14858
  • 作者列表:"Leo CH","Ng HH","Marshall SA","Jelinic M","Rupasinghe T","Qin C","Roessner U","Ritchie RH","Tare M","Parry LJ
  • 发表时间:2020-01-01
Abstract

BACKGROUND AND PURPOSE:Endothelium-derived vasoconstriction is a hallmark of vascular dysfunction in hypertension. In some cases, an overproduction of endothelium-derived prostacyclin (PGI2 ) can cause contraction rather than relaxation. Relaxin is well known for its vasoprotective actions, but the possibility that this peptide could also reverse endothelium-derived vasoconstriction has never been investigated. We tested the hypothesis that short-term relaxin treatment mitigates endothelium-derived vasoconstriction in spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH:Male Wistar Kyoto rats (WKY) and SHR were subcutaneously infused with either vehicle (20 mmol·L-1 sodium acetate) or relaxin (13.3 μg·kg-1 ·hr-1 ) using osmotic minipumps for 3 days. Vascular reactivity to the endothelium-dependent agonist ACh was assessed in vitro by wire myography. Quantitative PCR and LC-MS were used to identify changes in gene expression of prostanoid pathways and PG production, respectively. KEY RESULTS:Relaxin treatment ameliorated hypertension-induced endothelial dysfunction by increasing NO-dependent relaxation and reducing endothelium-dependent contraction. Notably, short-term relaxin treatment up-regulated mesenteric PGI2 receptor (IP) expression, permitting PGI2 -IP-mediated vasorelaxation. In the aorta, reversal of contraction was accompanied by suppression of the hypertension-induced increase in prostanoid-producing enzymes and reduction in PGI2 -evoked contractions. CONCLUSIONS AND IMPLICATIONS:Relaxin has region-dependent vasoprotective actions in hypertension. Specifically, relaxin has distinct effects on endothelium-derived contracting factors and their associated vasoconstrictor pathways in mesenteric arteries and the aorta. Taken together, these observations reveal the potential of relaxin as a new therapeutic agent for vascular disorders that are associated with endothelium-derived vasoconstriction including hypertension.

摘要

背景和目的: 内皮源性血管收缩是高血压血管功能障碍的标志。在某些情况下,内皮源性前列环素 (PGI2) 的过度产生可引起收缩而不是舒张。松弛素以其血管保护作用而闻名,但这种肽也可以逆转内皮源性血管收缩的可能性从未被研究过。我们检验了短期松弛素治疗缓解自发性高血压大鼠 (SHR) 内皮源性血管收缩的假设。 实验方法: 雄性 Wistar Kyoto 大鼠 (WKY) 和 SHR 皮下输注溶剂 (20 mmol · L-1 乙酸钠) 或松弛素 (13.3 μ g · kg-1 · hr-1) 使用渗透微量泵 3 天。通过线肌造影在体外评估血管对内皮依赖性激动剂 ACh 的反应性。定量 PCR 和 LC-MS 分别用于鉴定前列腺素类途径基因表达和 PG 产生的变化。 关键结果: 松弛素治疗通过增加 NO 依赖性舒张和减少内皮依赖性收缩改善高血压诱导的内皮功能障碍。值得注意的是,短期松弛素治疗上调肠系膜 PGI2 受体 (IP) 表达,允许 pgi2-ip 介导的血管舒张。在主动脉中,收缩逆转伴随着抑制高血压诱导的前列腺素生成酶增加和 PGI2 诱发的收缩减少。 结论和意义: 松弛素在高血压中具有区域依赖性血管保护作用。具体而言,松弛素对肠系膜动脉和主动脉的内皮源性收缩因子及其相关的血管收缩通路具有明显的作用。总之,这些观察结果揭示了松弛素作为一种新的血管疾病治疗药物的潜力,这些血管疾病与内皮源性血管收缩包括高血压有关。

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